Anticoagulants are useful therapeutic agents in the pharmacological treatment of, for example, acute deep venous thrombosis, pulmonary embolism, acute arterial embolization of the extremities, myocardial infarction, and disseminated intravascular coagulation. Prophylactic administration of anticoagulants is believed to prevent a recurrence of embolism in patients with rheumatic or arteriosclerotic heart disease and to prevent certain thromboembolic complications of surgery. Administration of anticoagulants has also been indicated in the treatment of coronary artery and cerebrovascular disease. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death.
Hirullin P18 is a 61-amino acid hirudin-related protein having potent antithrombin activity. Similar to hirudin, it contains a highly acidic C-terminus of significantly different sequence from any other known hirudin variant. The C-terminal fragment acetyl-hirullin P18.sub.40-61 has an antithrombin potency similar to that of acetyl-desulfatohirudin-.sub.45-65. While applicant has discovered that certain amino acids residues of the native sequence are critical to maintaining the antithrombin activity of the fragment, other residues have been found to be less important. Significant differences in the sequences of hirullin P18.sub.54-61 from hirudin.sub.59-65 suggest a different mode of interaction with thrombin. Nevertheless, the C-terminal functional domain represented by hirullin P18.sub.50-61 appears to be comparable to hirudin.sub.55-65 in terms of its binding to thrombin and its functional role in the protein.
Moreover, several reports have described the ability of the oligopeptide Arg-Gly-Asp and related peptides to inhibit the platelet-dependent thrombus formation. Y. Cadroy, et al., J. Clin. Invest. 84, 939-944 (1989). Applicant has discovered that when this oligopeptide is linked to the amino terminal end of the antithrombotic hirullin fragments, the resulting peptide analogs have significant and useful antiplatelet activity in addition to the antithrombotic activity. This new class of compounds should provide for a useful adjunct therapy due to the dual mode of action.